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Pathology week 22 – Liver and Biliary Tract ver.2

Liver

Normal

Functions:

- processes dietary amino acids, carbohydrates, lipids, vitamins

- removal of microbes and toxins in splanchnic blood en route to systemic circulation

- synthesis of many plasma proteins

- detoxification and excretion into bile of endogenous waste products and pollutant xenobiotics

Anatomy:

- right, left, caudate, and quadrate lobes

- eight segments, I to VIII, caudate lobe segment I and II to VIII, moving from left to right

- each segment has own independent vascular and biliary pedicle and venous drainage

- weighs 1400 to 1600 gm

- incoming blood-approximately 25% of total cardiac output-arrives via portal vein (60-70% of hepatic blood flow) and

hepatic artery (30-40%) through hilum (porta hepatis)

- key anatomical features – portal tracts (hepatic artery, portal vein, bile duct), hepatocellular parenchyma, hepatic veins

- between cords of hepatocytes are sinusoids lined by fenestrated endothelial cells

- scattered Kupffer cells (macrophages) attached to luminal face of endothelial cells

- stellate cells found in subendothelial space of Disse - play role in storage and metabolism of vitamin A and

transformed into collagen-producing myofibroblasts when there is inflammation

- zone 1 closest to blood supply, zone 3 farthest

Pathology

- primary diseases are viral hepatitis, alcoholic liver disease, and hepatocellular carcinoma

- hepatic damage secondary to common diseases - CHF, cancer, and extrahepatic infections

- enormous functional reserve masks clinical impact of early liver damage

Patterns of Hepatic Injury

Regardless of cause, five general responses seen:

Degeneration and Intracellular Accumulation - swelling of hepatocytes with fat, or water and solute

- moderate cell swelling is reversible

- certain materials can accumulate such as retained bile pigments, iron, copper or viral particles

Necrosis and Apoptosis

- coagulative necrosis due to ischaemia

- apoptosis due to toxic, viral or immunological injury

- lesions focal (scattered in parenchyma), zonal (periportal or perivenous), submassive, massive

- hepatocytes may osmotically swell and rupture, (lytic necrosis), due to ballooning degeneration

- necrosis frequently exhibits zonal distribution

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- necrosis immediately around terminal hepatic vein = centrilobular necrosis, characteristic of ischemic injury

and drug and toxic reactions

- periportal necrosis in eclampsia

Inflammation (hepatitis)

- influx of acute or chronic inflammatory cells into portal tracts or parenchyma

- foreign bodies, organisms, and some drugs may incite a granulomatous reaction

Regeneration

- occurs in all but most fulminant hepatic diseases

- hepatocellular proliferation marked by mitoses, thickening of hepatocyte cords, and some disorganization of

parenchymal structure

Fibrosis

- formed in response to inflammation or direct toxic insult

- fibrosis points toward generally irreversible hepatic damage (controversial)

- ongoing fibrosis - nodules of proliferating hepatocytes surrounded by scar tissue = "cirrhosis"

Hepatic Failure

- most severe end of liver disease spectrum

- occurs when >80% hepatic function lost

- mortality >80%

- often marginal function tipped towards decompensation if other illness/injury

- may require transplantation

Causes of hepatic failure:

- massive hepatic necrosis (fulminant viral hepatitis, hepatotoxic drugs and chemicals (paracetamol,halothane)

- chronic liver disease

- hepatic dysfunction without overt necrosis (tetracycling toxicity, Reyes syndrome, acute fatty liver of pregnancy,

mitochondrial dysfunction caused by HIV drugs)

Clinical features:

- hepatic dysfunction:

o jaundice and cholestasis

o hypoalbuminaemia

o hyperammonaemia

o hypoglycaemia

o fetor hepaticus (body odour due to mercaptan formation)

o hyperestrogenaemia (palmar erythema, spider angioma, hypogonadism, gynaecomastia)

o weight loss, muscle wasting

- portal hypertension:

o ascites

o splenomegaly

o haemorrhoids

o caput medusae

- life treatening complications:

o hepatic failure

� multi organ failure

� coagulopathy

� hepatic encephalopathy (↑ ammonia – disturbed consciousness, EEG changes, rigidity and

hyperreflexia, seizures, asterixis – flap – generalised brain oedema)

� hepatorenal syndrome (life-threatening renal failure without intrinsic renal pathology – decreased

renal perfusion, renal vasoconstriction, although renal concentrating ability maintained –

hyperosmolar urine low in sodium; reversible)

o portal hypertension from cirrhosis

� oesophageal varices, risk of rupture

o malignany with chronic disease

� hepatocellular carcinoma

Lab tests:

- hepatocyte integrity:

o cytosolic hepatocellular enzymes

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� aspartate aminotransferease (AST), alanine aminotransferase (ALT), LDH

- biliary excretory function:

o substances normally secreted in bile

� plasma bilirubin (total, direct – conjugated), urine bilirubin, serum bile acids

o plasma membrane enzymes (damage to bile canaliculus)

� alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), 5’-nucleotidase

- hepatocyte function

o proteins secreted into blood

� albumin. prothrombin time (factors V, VII, X, prothrombin, fibrinogen)

o hepatocyte metabolism

� ammonia

Cirrhosis

- amoung top 10 causes of death

- causes: alcohol (70%) and viral hepatitis, also biliary disease, haemochromatosis, Wilson disease, α1-AT deficiency,

cryptogenic cirrhosis (including autoimmune hepatitis and NASH)

- three characteristics:

� bridging fibrous septae: delicate bands or broad scars linking portal tracts with one another and portal

tracts with terminal hepatic veins (diffuse)

� parenchymal nodules containing proliferating hepatocytes encircled by fibrosis, varying from small (<3

mm, micronodules) to large (several cm, macronodules)

� disruption of architecture of liver

- fibrosis accompanied by vascular reorganization: abnormal interconnections between vascular inflow and hepatic vein

outflow channels, so portal vein and arterial blood partially bypasses functional hepatocyte mass through these

abnormal channels – underperfusion of liver

- also arterioportal venous shunts, arteriohepatic venous shunts, portal venous-hepatic venous sunts

Pathogenesis

- progressive fibrosis and reorganization of vascular microarchitecture of liver

- normal liver - interstitial collagens (types I, III) concentrated in portal tracts and around central veins, with

occasional bundles in space of Disse

- cirrhosis - types I and III collagen deposited in lobule, creating delicate or broad septal tracts

- new vascular channels in septae connect vascular structures in portal region (hepatic arteries and portal veins) and

terminal hepatic veins, shunting blood around parenchyma

- continued deposition of collagen (type IV) in space of Disse within preserved parenchyma accompanied by loss of

fenestrations in sinusoidal endothelial cells

- sinusoidal space comes to resemble a capillary rather than a channel for exchange of solutes between hepatocytes

and plasma - hepatocellular secretion of proteins (albumin, clotting factors, lipoproteins) greatly impaired

- pre-existing myofibroblasts creat some collage, but major source is perisinusoidal hepatic stellate cell (Ito cell)

(normally functioning as vitamin A fat-storing cells)

- stellate cells and myofibroblasts activated by:

� proinflammatory cytokines (eg TNFα, IL1) from chronic inflammation

� cytokine production by activated endogenous cells (Kupffer cells, endothelial cells, hepatocytes,

bile duct epithelial cells), including transforming growth factor-β (TGF-β), platelet-derived

growth factor (PDGF)

� disruption of ECM

� direct stimulation of stellate cells by toxins or portal tract myofibroblasts

- net result: fibrotic, nodular liver in which delivery of blood to hepatocytes is severely compromised, as is

ability of hepatocytes to secrete substances into plasma

- disruption of interface between parenchyma and portal tracts obliterates biliary channels, therefore

jaundice

Clinical Features:

- clinically silent for years

- anorexia, weight loss, weakness, oestoporosis

- death by hepatic failure, complications of portal hypertension, HCC

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Portal Hypertension

- increased resistance to portal blood flow, prehepatic, intrahepatic or posthepatic

- prehepatic:

� obstructive thrombosis and narrowing of portal vein before ramifies within liver

� massive splenomegaly may shunt excessive blood into splenic vein

- posthepatic:

� RHF, constrictive pericarditis, hepatic vein outflow obstruction (Budd-Chiari )

- intrahepatic:

� cirrhosis, accounting for most cases of portal hypertension

� less frequent - schistosomiasis, massive fatty change, diffuse fibrosing granulomatous disease

such as sarcoidosis and miliary tuberculosis, and diseases affecting portal microcirculation,

exemplified by nodular regenerative hyperplasia

Clinical consequences:

(1) ascites

(2) formation of portosystemic venous shunts

(3) congestive splenomegaly

(4) hepatic encephalopathy

Ascites

- collection of excess serous fluid in peritoneal cavity, usually detectable >500mL

- serous fluid, less than 3 gm/dL of protein (largely albumin) as well as same concs of glucose, sodium, and

potassium as blood

- influx of neutrophils suggests secondary infection, red cells point to disseminated Ca

- pathogenesis:

� hepatic sinusoidal hypertension, drives fluid into space of Disse

� percolation of lymph into peritoneal cavity, exceeds thoracic duct capacity

� intestinal fluid leakage into peritoneal cavity (increased perfusion pressure in intestinal

capillaries and osmotic action of protein-rich ascitic fluid)

� renal retention of sodium and water (secondary hyperaldosteronism)

Portosystemic Shunts

- with rise in portal system pressure, bypasses develop wherever systemic and portal circulation share

common capillary beds

- sites:

� veins around and within rectum (haemorrhoids)

� cardioesophageal junction (esophagogastric varices)

� retroperitoneum, and falciform ligament of liver (involving periumbilical and abdominal wall

collaterals - caput medusae)

Splenomegaly

- caused by longstanding congestion

- can cause haematological abnormalities due to hypersplenism

Jaundice and Cholestasis

- bile serves two major functions: (1) emulsification dietary fat in gut (2) elimination waste products

- primary pathway for elimination of bilirubin, excess cholesterol, and xenobiotics that are insufficiently water-soluble to

be excreted into urine

- jaundice = yellow skin, icterus = yellow sclerae

- cholestasis =systemic retention of bilirubin, bile salts and cholesterol

Bilirubin metabolism and elimination

- bilirubin end product of haem degradation

- haem oxygenase oxidizes heme to biliverdin, then reduced to bilirubin by biliverdin reductase

- bilirubin bound to serum albumin (small amount unbound, increased in haemolytic disease or if drugs displace bilirubin

from albumin)

- into liver where conjugated with glucuronic acid by bilirubin UDP-glucuronyltransferase -UGT1A1

- water-soluble, nontoxic bilirubin glucuronides excreted into bile

- deconjugated by bacterial β-glucuronidases and degraded to colorless urobilinogens

- largely excreted in faeces

- approx 20% of urobilinogens reabsorbed in ileum and colon, returned to liver, re-excreted into bile

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Pathophysiology of Jaundice

- occurs when bilirubin production excees hepatic clearance capacity

- unconjugated or conjugated hyperbilirubinaemia

- unconjugated bilirubin virtually insoluble in water, complexed to albumin

� cannot be excreted in urine

� very small amount unbound present

� may diffuse into tissues, esp brain in infants, produce toxic injury

� may ↑ in haemolytic disease or when drugs displace bilirubin from albumin

� haemolytic disease of newborn (erythroblastosis fetalis) may lead to accumulation of

unconjugated bilirubin in brain, can cause severe neurologic damage - kernicterus

- conjugated bilirubin water soluble, nontoxic, only loosely bound to albumin

� excess conjugated bilirubin can be excreted in urine

Causes of jaundice:

(1) excessive production of bilirubin

(2) reduced hepatocyte uptake

(3) impaired conjugation

(4) decreased hepatocellular excretion

(5) impaired bile flow (intrahepatic and extrahepatic)

1-3 produce unconjugated hyperbilirubinemia, 4-5 produce conjugated hyperbilirubinemia

- > one mechanism may operate to produce jaundice, especially hepatitis, which can produce unconjugated and conjugated

- commonly due to bilirubin overproduction (haemolytic anaemias, resorption haemorrhage), hepatitis, obstruction to bile

Causes of Jaundice

Predominantly Unconjugated Hyperbilirubinemia

Excess production bilirubin (haemolytic anaemia, resorption internal bleed, ineffective erythropoiesis eg thalassemia)

Reduced hepatic uptake (drugs (eg rifampicin) interfering with membrane carriers, Gilberts)

Impaired bilirubin conjugation

Physiologic jaundice of the newborn (transient decrease UGT1A1 activity, decreased excretion)

Breast milk jaundice (β-glucuronidases in milk)

Genetic deficiency of UGT1A1 activity (Crigler-Najjar syndrome types I and II)

Gilbert syndrome (mixed etiologies)

Diffuse hepatocellular disease (viral or drug-induced hepatitis, cirrhosis)

Predominantly Conjugated Hyperbilirubinemia

Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)

Impaired bile flow

Cholestasis

- result from hepatocellular dysfunction or intrahepatic or extrahepatic biliary obstruction

- may present with jaundice, pruritus - elevation in plasma bile acids/deposition in skin, xanthomas (focal

accumulations of cholesterol) – due to hyperlipidemia and impaired excretion of cholesterol

- elevated ALP (present in bile duct epithelium and canalicular membrane of hepatocytes released into circulation

because of detergent action of retained bile salts on hepatocyte membranes) (isozyme different from bone)

- elevated GGT, reflects detergent action of bile salts retained in luminal space of the bile canaliculus on apical

membranes of hepatocytes and bile duct epithelial cells

- intestinal malabsorption - deficiencies of fat-soluble vitamins A, D, or K

- morphology: accumulation of pigment in hepatic parenchyma – can form bile lakes - and distension of upstream bile

ducts – can lead to portal tract fibrosis (biliary cirrhosis)

- intrahepatic obstruction can’t be treated by surgery – need transplant

Familial Intrahepatic Cholestasis:

- heterogeneous group of autosomal-recessively inherited cholestatic conditions

- characterized by low bile salt secretion into bile so severe impairment of bile formation

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- eg. benign recurrent intrahepatic cholestasis (BRIC), there are intermittent attacks of cholestasis over life without

progression to chronic liver disease

- eg. progressive familial intrahepatic cholestasis 1 (PFIC-1), cholestasis begins in infancy with severe pruritus due to

high serum bile acid levels and relentlessly progresses to liver failure before adulthood

Infectious Disorders

Most hepatic infections viral; also miliary tuberculosis, malaria, staphylococcal, salmonella, candida, and amebiasis

Viral Hepatitis

- infection of liver caused by viruses with particular affinity for liver

- systemic viral infections can also affect live: EBV, CMV, yellow fever

The Hepatitis Viruses

Hep A Virus Hep B Virus Hep C Virus Hep D Virus Hep E Virus

Hep G

Virus

Agent Icosahedral

capsid, ssRNA

Enveloped

dsDNA

Enveloped

ssRNA

Enveloped ssRNA Unenveloped

ssRNA

ssRNA

virus

Transmission Faecal-oral Parenteral;

close contact

Parenteral;

close contact

Parenteral; close

contact

Waterborne Parenteral

Incubation period 2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown

Carrier state None 0.1-1.0%

blood donors

0.2-1.0%

blood donors

1-10% IVDU,

haemophiliacs

Unknown 1-2% blood

donors

Chronic hepatitis None 5-10% of

acute

infections

>50% <5% coinfxn, 80%

superinfxn

None None

Hepatocellular

carcinoma

No Yes Yes No increase above

HBV

Unknown,

unlikely

None

Hepatitis A Virus (HAV)

- benign, self-limited disease with incubation period 2 - 6 weeks

- does not cause chronic hepatitis or carrier state, only rarely causes fulminant hepatitis

- low fatality rate (worse if also have Hep B/C/EtOH)

- occurs throughout world, endemic in countries with substandard hygiene

- small, nonenveloped, single-stranded RNA picornavirus

- icosahedral capsid 27 nm in diameter

- spread by ingestion of contaminated water and foods, shed in stool for 2 - 3 weeks before and 1 week after

onset of jaundice

- close contact or faecal-oral contamination

Serologic Diagnosis:

- specific antibody against HAV of Ig M type appears in blood at onset of symptoms

- faecal shedding of virus ends as IgM titer rises

- IgM response begins to decline in a few months, followed by appearance of IgG anti-HAV, which persists

for years, perhaps for life, providing protective immunity

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Hepatitis B Virus (HBV)

Can produce:

(1) acute hepatitis with resolution

(2) chronic hepatitis, which may evolve to cirrhosis

(3) fulminant hepatitis with massive liver necrosis

(4) backdrop for hepatitis D virus infection

- patients with chronic hepatitis represent carriers of actively replicating virus, so source of infection

- important role in the development of hepatocellular carcinoma

- circulating host IgG antibodies effectively neutralize HBV, so HBV vaccine highly effective

- prolonged incubation period (4 to 26 weeks)

- unlike HAV, HBV remains in blood up to and during active episodes of acute and chronic hepatitis

- present in all physiologic and pathologic body fluids, with exception of stool

- blood and body fluids are primary vehicles of transmission, but also spread by virus body secretions such as semen, saliva,

sweat, tears, breast milk, and pathologic effusions

- high risk: transfusion, blood products, dialysis, needle-stick accidents, IVDU, homosexual activity

- also spread from infected mother to neonate during birth (vertical transmission)

- HBcAg = hepatitis B core Ag, HBeAg = hepatitis B "e" Ag, HBsAg = hepatitis B surface Ag

- because of HBV DNA integrated into host genome, risk of hepatocellular carcinoma

- HBV is not directly toxic to liver cells; instead it is the immune response to viral antigens, expressed on infected

hepatocytes, that cause liver cell injury

- HBV evokes both a humoral and cellular immune response, the latter involving both CD4+ helper T cells and CD8+

cytotoxic T cells

- trmt: IFN-α, antivirals

Sequence of serological markers for Hep B demonstrating A – acute infection with resolution, B – progression to chronic

infection:

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Serologic Diagnosis:

- asymptomatic 4- to 26-week incubation period

- acute disease lasting many weeks to months

� HBsAg appears before onset of symptoms, peaks during overt disease, declines to undetectable

levels in 3 to 6 months

� HBeAg, HBV-DNA, and DNA polymerase appear in serum soon after HBsAg, all signify active

viral replication

� IgM anti-HBc detectable in serum shortly before onset of symptoms, concurrent with onset of

elevation of serum aminotransferases; over months, IgM antibody replaced by IgG anti-HBc

� Anti-HBe detectable shortly after disappearance of HBeAg, implying that acute infection has

peaked and disease is on the wane

� IgG anti-HBs does not rise until acute disease is over and usually not detectable for a few weeks

to several months after disappearance of HBsAg

� Anti-HBs may persist for life, conferring protection

- carrier state = presence of HBsAg in serum for >6 months after initial detection

Hepatitis C Virus (HCV)

- a major cause of liver disease

- most common chronic blood-borne infection, accounts for almost half of all patients with chronic liver

disease

- major routes of transmission: inoculations and blood transfusions

� IVDU 60%

� transfusions prior to 1991 10%

� haemodialysis/health care workers/haemophiliacs < 5%

� sexual transmission 15%

� perinatal transmission risk lower than Hep B

� acute HCV infection generally undetected clinically

- like Hep B, liver damage is immune-mediated

- trmt: interferon, ribaviran – partial efficacy; no vaccine available

Serologic Diagnosis:

- incubation period 2 to 26 weeks

- HCV RNA detectable in blood for 1 to 3 weeks, coincident with elevations in transaminases

- symptomatic acute HCV infection - anti-HCV antibodies detected in only 50-70%

- asymptomatic infection - anti-HCV antibodies emerge after 3 to 6 weeks

- clinical course of acute HCV hepatitis milder than HBV

- rare cases may be severe and indistinguishable from HAV or HBV

- chronic HCV infection - circulating HCV RNA persists despite presence of neutralizing antibodies – in more than

90% of patients with chronic disease

- characteristic of chronic HCV infection is episodic elevations in serum aminotransferases, with intervening normal or

near-normal periods

Sequence of serological markers for Hep C demonstrating: A – acute infection with resolution, B – progression to chronic

relapsing infection:

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Hepatitis D Virus (HDV) aka delta hepatitis

- defective RNA virus that can replicate and cause infection only when encapsulated by HBsAg (causes

hepatitis only in presence of HBV)

- arises in two settings:

� acute coinfection following exposure to serum containing both HDV and HBV

� results in hepatitis ranging from mild to fulminant

� superinfection of chronic carrier HBV with new inoculum of HDV

� 3 possible outcomes:

� 1. acute, severe hepatitis in previously healthy HBV carrier

� 2. mild HBV hepatitis converted to fulminant disease

� 3. chronic, progressive disease (80%), culminating in cirrhosis

- higher risk HBV + HDV together in IVDU and haemophiliacs that others at risk of HBV

Clinical consequences of two patterns of combined hepatitis D virus and hepatitis B virus infection:

Serologic Diagnosis:

- HDV RNA detectable in blood just prior to and in early days of acute symptomatic disease

- IgM anti-HDV most reliable indicator of recent HDV exposure, appearance is late and short-lived

- acute coinfection by HDV and HBV best indicated by detection of IgM against both HDAg and HBcAg (denoting

new infection with hepatitis B)

- in chronic delta hepatitis arising from HDV superinfection, HBsAg is present in serum, and IgM anti-HDV persists

for months or longer

Sequence of serologic markers for Hep D showing – A: coinfection, B - superinfection:

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Hepatitis E Virus (HEV)

- enteric transmitted, water-borne infection occurs in young to middle-aged adults

- epidemics in Asia/India/Africa, sporadic infection in travelers

- high mortality rate among pregnant women

- most cases self-limiting, not associated with chronic liver disease or persistent viremia

- average incubation period 6 weeks

- specific antigen (HEV Ag) identified in cytoplasm of hepatocytes during active infection, and virions

shed in stool during the acute illness

Serologic Diagnosis:

- before onset of clinical illness, HEV RNA and HEV virions detected in stool and liver

- onset of rising aminotransferases, clinical illness, and elevated IgM anti-HEV titers virtually simultaneous

- symptoms resolve in 2-4 weeks, and IgM replaced with persistent IgG anti-HEV titer

Other Hepatitis Viruses

- no F agent identified

- HGV transmitted by contaminated blood or blood products and possibly sexual contact

� up to 75% of infections, HGV cleared from plasma

� remainder of cases, HGV infection becomes chronic

� site of HGV replication most likely mononuclear cells

� does not cause elevations in serum aminotransferases

� no pathologic effects of HGV

� virus commonly co-infects patients with HIV - dual infection somewhat protective against HIV

disease

Clinicopathologic Syndromes

- a number of clinical syndromes develop following exposure to hepatitis viruses:

� acute asymptomatic infection with recovery: serologic evidence only

� acute symptomatic hepatitis with recovery: anicteric or icteric

� chronic hepatitis: without or with progression to cirrhosis

� fulminant hepatitis: with massive to submassive hepatic necrosis

Acute Infection with Recovery

- similar for all hep viruses, variable incubation periods, asymptomatic preicteric phase, symptomatic

icteric phase, convalescence

- fulminant course in >1%

- can be subclinical

- drug reactions can mimic acute hepatitis

Chronic Hepatitis

- symptomatic, biochemical or serological evidence of ongoing hepatic inflammation

- >6 months without recovery

- major causes: viral, Wilson disease, α1AT deficiency, alcohol, drugs, autoimmunity

- likelihood of developing chronic hepatitis:

� HAV – none

� HBV - >90% infected neonates, 10% adults

� HCV - >60% (half then progress to cirrhosis)

� HDV – rare in coinfection, frequent in superinfection of pt with HBV

� HEV – none

- occas in HBV and HCV, immune complex disease may develop secondary to presence of circulating

antibody-antigen complexes - vasculitis and glomerulonephritis; cryoglobulinemia found in 35% of

chronic HCV

Carrier state

- individual without manifest symptoms who harbours and therefore can transmit virus

- two types:

� little or no adverse effects (healthy carriers)

� chronic disease but few or no symptoms

- carrier states:

� HAV and HEV – none

� HBV – 90% infants, 1-10% adults

� HCV - <1% healthy carriers

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� HDV – low potential for carrier state

Fulminant Hepatitis

- hepatic insufficiency with hepatic encephalopathy 2-3 wks after onset of symptoms

- 12% cases viral, 50% durg/chemical toxicity, 18% unknown cause

- mortality 25-90% without transplant

Morphology

- acute viral hepatitis:

- slightly enlarged and green

- hepatocyte necrosis ranging from hepatocytes to clumps to lobules

- necrotic hepatocytes eosinophilic/rounded (undergoing apoptosis) or swollen (ballooning degeneration)

- lymphocytes present and macrophages engulf necrotic hepatocytes

- architecture disrupted by necrosis, portal – to – central (bridging) necrosis if severe

- kupffer cells and sinusoidal lining cells hypertrophied and hyperplasia

- portal tract inflammation (lymphocytes and macrophages), hepatocellular regeneration and occas cholestasis

- chronic hepatitis:

- ranges mild to severe to cirrhosis

- mild: chronic inflam infiltrate in portal tracts only

- progresses to chronic inflam into parenchyma with hepatocyte necrosis (interface hepatitis)

- bridging necrosis

- continued loss of hepatocytes results in fibrous septum formation

- hepatocyte regeneration results in cirrhosis

- carrier state for HBV:

- may have normal liver

- some cells may show granular, eosinophilic cytoplasm (ground glass)

- stain positive for HBsAg on electron microscopy

- HCV-infected patients show chronic hepatitis

- fulminant hepatitis:

- liver shrunken

- affected areas soft, red or bile-stained

- lobules destroyed leaving collapsed reticulin network

- inflammation may be minimal

- in massive destruction may look like cirrhosis

Bacterial, Parasitic and Helminthic Infections

- extrahepatic infections, particularly sepsis, can induce mild hepatic inflammation

- hepatocellular cholestasis in sepsis due to effects of pro-inflammatory cytokines released by Kupffer cells

and endothelial cells in response to circulating endotoxin

- bacteria can infect the liver directly: Staph aureus in toxic shock syndrome, Salmonella typhi in typhoid

fever, and secondary or tertiary syphilis

- bacteria may proliferate in biliary tree compromised by obstruction - cholangitis

- liver involvement in malaria, schistosomiasis, strongyloidiasis, cryptosporidiosis, leishmaniasis,

echinococcus, and infections by liver flukes

- liver abscess: common in developing countries - most represent parasitic infections

- in developed countries tend to be bacterial – portal spread from abdo infections, biliary tree or arterial

supply in those with immune deficiency

- organisms reach liver by

� (1) portal vein

� (2) arterial supply

� (3) ascending infection in biliary tract (ascending cholangitis)

� (4) direct invasion of liver from nearby source

� (5) penetrating injury

- fever, RUQ pain, tender hepatomegaly, possible jaundice

Autoimmune Hepatitis

- chronic hepatitis, histologic features indistinguishable from chronic viral hepatitis

� portal and lobular infiltrates lymphocytes and plasma cells

- female predominance (78%), particularly young and perimenopausal; 1.9 per 100,000

- absence of viral serologic markers, elevated IgG and γ-globulin levels

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- high serum titers of autoantibodies in 80% of cases - ANA, SMA, antiliver/kidney microsomes (anti-

LKM1) antibodies

- negative antimitochondrial antibody (AMA)

- other forms autoimmune disease in 60% (RA, thyroiditis, Sjögren syndrome, UC)

- trmt: immunosuppressives, liver transplant

Drug- and Toxin-Induced Liver Disease

- liver is major drug metabolizing and detoxifying organ in body

- injury may result:

� (1) from direct toxicity

� (2) via hepatic conversion of xenobiotic to active toxin

� (3) through immune mechanisms, usually by a drug or a metabolite acting as a hapten to convert

a cellular protein into an immunogen

Drug- and Toxin-Induced Hepatic Injury

Hepatocellular Damage Examples

Microvesicular fatty change • Tetracycline, salicylates, ethanol

Macrovesicular fatty change • Ethanol, methotrexate, amiodarone

Centrilobular necrosis • Bromobenzene, CCl4, acetaminophen, halothane, rifampin

Diffuse or massive necrosis • Halothane, isoniazid, acetaminophen, methyldopa, mushroom toxin

Hepatitis, acute and chronic • Methyldopa, isoniazid, nitrofurantoin, phenytoin

Fibrosis-cirrhosis • Ethanol, methotrexate, amiodarone, most drugs that cause chronic

hepatitis

Granuloma formation • Sulfonamides, methyldopa, quinidine, hydralazine, allopurinol

Cholestasis (w/ wout hepatocellular injury) • Chlorpromazine, steroids, erythromycin, oral contraceptives

Injury may take form of:

� hepatocyte necrosis

� hepatitis

� cholestasis

� fibrosis

� insidious onset of liver dysfunction

Alcoholic Liver Disease

Leading cause of liver disease in most Western countries

Chronic alcohol consumption - variety of adverse effects - three distinctive, overlapping, forms of liver disease (collectively

referred to as alcoholic liver disease):

(1) hepatic steatosis (fatty liver)

- initially small (microvescicular) lipid droplets accum within hepatocytes with mod EtOH intake

- with chronic intake, macrovescicular droplets displace the nucleus

- liver enlarged, soft, greasy, yellow

- no fibrosis, reversible

(2) alcoholic hepatitis

- liver cell necrosis (ballooning degeneration and apoptosis), particularly centriblobular

- Mallory body formation (intracellular eosinophilic aggregates of intermediate filaments)

- neutrophilic reaction to degenerating hepatocytes

- portal inflammation that spills into lobules

- fibrosis (sinusoidal, pericentral and periportal)

(3) cirrhosis

- final and irreversible outcome of alcoholic liver disease

- brown, shrunken, nonfatty

- regenerative nodules prominent or buried in fibrous scar

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Pathogenesis:

- steatosis results from shunting of substrates toward lipid biosynthesis, impaired lipoprotein assembly and

secretion, and increased peripheral catabolism of fat

- cellular injury results from:

� induction of cytochromes P-450, esp CYP2E1 – augmenting catabolism of other drugs to

potentially toxic metabolites (eg panadol)

� free radicals generated by microsomal ethanol oxidizing system

� acetaldehyde generated from EtOH to induce lipid peroxidation and acetaldehyde-protein adduct

formation

� impaired hepatic metabolism of methionine leads to decreased intrahepatic glutathione (GSH)

levels, sensitizing liver to oxidative injury

- alcohol induces immunological attack on hepatic neoantigens

- alcohol is a caloric food source, displacing nutrients

- fibrosis is the result of collagen deposition by perisinusoidal stellate cells, causing cirrhosis; stimuli

include:

� Kupffer cell activation (with proinflammatory cytokine release)

� amplification of cytokine stimuli by PAF

� influx of neutrophils into parenchyma, releasing free radicals, proteases and other inflammatory

mediators

- deranged hepatic blood flow is the result of progressive fibrosis and alcohol-induced release of

vasocontrictive endothelins from sinusoidal endothelial cells

Therefore: alcoholic liver disease is a chronic disorder of steatosis, hepatitis, progressive fibrosis, cirrhosis, and marked

derangement of vascular perfusion.

Maladaptive state in which cells in liver respond in an increasingly pathologic manner to a stimulus (alcohol) that originally

was only marginally harmful.

Clinical Features:

Hepatic steatosis:

- no evidence or hepatomegaly, mild elevation of bilirubin and ALP

- reversible with abstinence

Alcoholic hepatitis:

- acute, following bout of heavy drinking

- symptoms minimal or those of fulminant hepatic failure

- nonspecific symptoms of malaise, anorexia, weight loss, upper abdominal discomfort, tender

hepatomegaly, and hyperbilirubinemia, elevated ALP, neutrophilic leukocytosis

- acute cholestatic syndrome may appear, resembling large bile duct obstruction

- repeated bouts - cirrhosis appears in about one third

- may be reversible or progresses to cirrhosis despite abstinence

Alcoholic cirrhosis:

- manifestations similar to those of other forms of cirrhosis

- first signs of cirrhosis can relate to complications of portal hypertension, including bleed

- malaise, weakness, weight loss, loss of appetite then jaundice, ascites, peripheral oedema, due to impaired

synthesis of albumin

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- stigmata of cirrhosis (grossly distended abdomen, wasted extremities, caput medusae)

- elevated AST, ALT, ALP, bilirubin, hypoproteinemia (globulins, albumin, clotting factors), and anaemia

- may be clinically silent, discovered at autopsy or when stress such as infection

End-stage alcoholic cirrhosis, causes of death:

(1) hepatic coma

(2) a massive gastrointestinal hemorrhage

(3) an intercurrent infection

(4) hepatorenal syndrome

(5) hepatocellular carcinoma in 3-6% of cases

Metabolic Liver Disease

Non-Alcoholic Fatty Liver Disease (NAFL) and Steatohepatitis

- NAFL resembles alcohol-induced liver disease but occurs in patients who are not heavy drinkers

- strong associations with obesity, dyslipidemia, hyperinsulinemia and type 2 diabetes

- diagnosis of exclusion

- most likely explanation for elevated aminotransferases and/or GGT

- liver biopsy findings of steatosis – vesicles of fat in hepatocytes

- most common cause of “cryptogenic” cirrhosis

- steatohepatitis (nonalcoholic steatohepatitis, or NASH) (steatosis and inflammation)

- liver biopsy shows steatosis, multifocal parenchymal inflammation, Mallory hyaline, hepatocyte death (both ballooning

degeneration and apoptosis), and sinusoidal fibrosis

- cirrhosis may occur

Haemachromatosis

- excessive accum body iron, most deposited in parenchymal organs such as liver and pancreas

- results either from genetic defect causing excessive iron absorption or consequence of parenteral administration of iron

(transfusions)

- hereditary haemochromatosis - homozygous-recessive

� HH allele 6% population

� gene HFE on chr 6, encodes HLA-class I - like molecule, regulates intestinal absorption dietary

iron

� C282Y mutation (cysteine to tyrosine substitution)

� M:F 6:1 (menstrual loss/pregnancy in women)

� presents age 20-30 with hepatomegaly, abdo pain, pigmentation, DM, cardiac dysfunction

(arrhythmias, cardiomyopathy), arthritis, hypogonadism

� complications: cirrhosis (incl HCC – 200x risk) and cardiac

� trmt: phlebotomy; screening of family members of probands

- acquired forms of haemochromatosis called secondary haemochromatosis

Classification of Iron Overload

I. Hereditary Haemochromatosis

II. Secondary Haemochromatosis A. Parenteral iron overload

� Transfusions (haemodialysis, aplastic anaemia, sickle cell, myelodysplasia, leukaemia)

� Iron-dextran injections

B. Ineffective erythropoiesis with increased erythroid activity

� β-Thalassemia, Sideroblastic anaemia, Pyruvate kinase deficiency

C. Increased oral intake of iron

African iron overload (Bantu siderosis)

D. Congenital atransferrinemia

E. Chronic liver disease

Chronic alcoholic liver disease

Porphyria cutanea tarda

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Excessive iron directly toxic to host tissues by following mechanisms:

(1) lipid peroxidation via iron-catalyzed free radical reactions

(2) stimulation of collagen formation

(3) interaction reactive oxygen species + iron with DNA, lead to lethal injury or predisposition to HCC

Morphologic changes:

(1) deposition of hemosiderin in liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid and parathyroid

glands, synovial joints, and skin

(2) cirrhosis

(3) pancreatic fibrosis

Wilson Disease

- autosomal-recessive disorder

- accumulation of toxic levels of copper in many tissues and organs, principally liver, brain and eye

(hepatolenticular degeneration)

Pathogenesis:

- genetic defect ATP7B gene, chr 13, encodes hepatocyte canalicular membrane transmembrane copper-

transporting ATPase

- copper absorption and delivery to liver normal but increased hepatic export into circulation due to

defective secretion of copper into bile

- copper-related injury include poisoning of hepatic enzymes, abnormal binding of copper to serum proteins

and free radical formation

- usually by 5 years non-ceruloplasmin-bound copper spills over from liver into circulation, causing

haemolysis and pathologic changes at other sites such as brain, corneas, kidneys, bones, joints, and

parathyroids

Morphology:

- liver damage minor to severe: fatty change, acute and chronic hepatitis (with Mallolry bodies), cirrhosis and (rarely)

massive liver necrosis; tends to affect basal ganglia

- eye lesions – Kayser-Fleischer rings (green-brown copper deposits in corneal limbus)

- neuropsychiatric disorders: behavioural, psychosis, Parkinsonism

- labs: ↓ ceruloplasmin (copper-binding protein), ↑ hepatic copper content, ↑ urinary copper excretion

- serum copper levels not helpful

- trmt: copper chelation (D-penicillamine), transplant

α1- Antitrypsin Deficiency

- autosomal-recessive → smoking synergistic with lung damage

- abnormally low serum levels of this protease inhibitor

- major function is inhibition of proteases, particularly elastase, cathepsin G, and proteinase 3, which are

normally released from neutrophils at sites of inflammation

- deficiency leads to pulmonary emphysema and liver disease

- HCC in 3% of PiZZ adults

Neonatal Cholestasis

- prolonged conjugated hyperbilirubinemia in neonate, 1 in 2500 live births

- major conditions causing:

(1) cholangiopathies, primarily biliary atresia

(2) disorders causing conjugated hyperbilirubinemia in neonate, collectively neonatal hepatitis

(3) idiopathic

Major Causes of Neonatal Cholestasis

Bile duct obstruction (biliary atresia)

Neonatal infection (CMV, bacterial sepsis, UTI, syphilis)

Toxic (drugs, parenteral nutrition)

Metabolic disease (tyrosinaemia, Niemann-Pick disease, galactosaemia, defect bile aid synthetic pathways, α1-AT, CF)

Miscellaneous (shock, hypoperfusion, Indian childhood cirrhosis, alagille syndrome (paucity of bile ducts)

Idiopathic neonatal hepatitis

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Intrahepatic Biliary Tract Disease

- secondary biliary cirrhosis, primary biliary cirrhosis, and primary sclerosing cholangitis

Distinguishing Features of the Major Intrahepatic Bile Duct Disorders

Secondary Biliary Cirrhosis Primary Biliary Cirrhosis Primary Sclerosing Cholangitis

Aetiology Extrahepatic bile duct

obstruction: biliary atresia,

gallstones, stricture,

carcinoma of pancreatic head

Possibly autoimmune Unknown, possibly autoimmune;

50-70% associated with

inflammatory bowel disease

Sex predilection

Symptoms and signs

None Pruritus, jaundice,

malaise, dark urine, light

stools, hepatosplenomegaly

Female to male: 6:1 Same as

secondary biliary cirrhosis;

insidious onset

Female to male: 1:2 Same as

secondary biliary cirrhosis;

insidious onset

Laboratory findings Conjugated

hyperbilirubinemia, increased

serum alkaline phosphatase,

bile acids, cholesterol

Same as secondary biliary

cirrhosis, plus elevated serum

IgM autoantibodies

(especially M2 form of

antimitochondrial antibody-

AMA)

Same as secondary biliary

cirrhosis, plus elevated serum

IgM, hypergammaglobulinemia

Important pathologic

findings before cirrhosis

develops

Prominent bile stasis in bile

ducts, bile ductular

proliferation with

surrounding neutrophils,

portal tract edema

Dense lymphocytic infiltrate

in portal tracts with

granulomatous destruction of

bile ducts

Periductal portal tract fibrosis,

segmental stenosis of

extrahepatic and intrahepatic bile

ducts

Secondary Biliary Cirrhosis

- prolonged obstruction of extrahepatic biliary tree results in profound alteration of liver

- most common cause of obstruction in adults is extrahepatic cholelithiasis, then malignancies

- in children: biliary atresia, cystic fibrosis, choledochal cysts

- secondary inflammation resulting from biliary obstruction initiates periportal fibrosis

- risk of ascending cholangitis

Primary Biliary Cirrhosis

- chronic, progressive, often fatal cholestatic liver disease

- primary feature is nonsuppurative, inflammatory destruction of medium-sized intrahepatic bile ducts

- primarily a disease of middle-aged women, F:M 6:1

- hepatomegaly, jaundice, xanthomas, malabsorption, stigmata of chronic liver disease late

- 90% have antimitochondial antibodies against E2 subunit of pyruvate dehydrogenase complex (PDC-E2),

dihydrolipoamide acetyltransferase (autoimmune)

- small-duct biliary fibrosis and cirrhosis

Primary Sclerosing Cholangitis

- inflam and obliterative fibrosis of intra + extrahepatic bile ducts, with dilation of preserved segments

- irregular strictures and dilations of affected bile ducts

- association with IBD esp UC, but cause unknown

- M:F 2:1

- secretion of proinflammatory cytokines by activated hepatic macrophages followed by infiltration of T cells into stroma

immediately around bile ducts

- autoantibodies present in less than 10% of patients

- increased risk cholangiocarcinoma

Anomalies of the Biliary Tree

- Von Meyenburg Complexes - small clusters modestly dilated bile ducts embedded in fibrous, sometimes hyalinized stroma

- Polycystic Liver Disease - multiple diffuse cystic lesions

- Congenital Hepatic Fibrosis - portal tracts are enlarged by irregular and broad bands of collagenous tissue, forming septa

and dividing liver into irregular islands

- Caroli Disease - larger ducts of intrahepatic biliary tree segmentally dilated and may contain bile

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Circulatory Disorders

- disorders grouped according to whether blood flow into, through, or from liver is impaired

Impaired blood flow into the liver

Hepatic Artery Compromise

- liver infarcts rare due to double blood supply

- thrombosis/compression branch of hepatic artery by embolism, neoplasia, polyarteritis nodosa, or sepsis

- retrograde arterial flow through accessory vessels, with portal venous supply, usually sufficient

Portal Vein Obstruction and Thrombosis

- blockage of extrahepatic portal vein insidious and well tolerated or catastrophic and potentially lethal

- produces abdominal pain, ascites and other manifestations of portal hypertension, principally esophageal

varices which are prone to rupture

- acute impairment of visceral blood flow leads to congestion and bowel infarction

- can be due to sepsis, thromboses (eg postop), trauma, pancreatitis or idiopathic

Impaired blood flow through the liver

- most common intrahepatic cause of blood flow obstruction is cirrhosis

- physical occlusion of sinusoids - sickle cell disease, DIC, eclampsia, metastatic cells

- obstruction to blood flow and massive necrosis of hepatocytes can lead to fulminant hepatic failure

- systemic circulatory compromise

� shock or LHF – causes centrolobular necrosis (ischaemic necrosis)

� RHF – passive congestion of liver

Peliosis Hepatis

- sinusoidal dilation occurs in any condition where efflux of hepatic blood is impeded

- Peliosis hepatitis:

� rare condition in which dilation is primary

� most commonly associated with anabolic steroids, OCP and danazol

� pathogenesis not known

� signs absent even in advanced peliosis

� reversible

Hepatic Venous Outflow Obstruction

Hepatic Vein Thrombosis and Inferior Vena Cava Thrombosis

- clinically silent if single main hepatic vein thrombosed

- obstruction 2 or more – hepatomegaly, pain, ascites (Budd-Chiari syndrome)

- results: ↑ intrahepatic BP, inability hepatic blood flow to shunt around blocked outflow

- associated with myeloproliferative disorders (incl polycythemia), inherited disorders coagulation

(deficiencies antithrombin, protein S or C, or mutations factor V), antiphospholipid syndrome, paroxysmal

nocturnal haemoglobinuria, intra-abdominal cancers, particularly HCC, pregnancy, OCP

- IVC thrombosis at its hepatic portion (obliterative hepatocavopathy)

� may arise from thrombogenic disorders, frequently idiopathic

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Veno-Occlusive Disease (Sinusoidal Obstruction Syndrome)

- occurs primarily in immediate weeks following bone marrow transplantation

- 25% in recipients of allogeneic marrow transplants, mortality rates over 30%

- tender hepatomegaly, ascites, weight gain, and jaundice

Hepatic Disease Associated with Pregnancy

- viral hepatitis most common cause of jaundice in pregnancy

- hepatitis E more severe course in pregnancy

- 0.1% develop hepatic complications directly attributable to pregnancy:

� preeclampsia, acute fatty liver of pregnancy, intrahepatic cholestasis

Preeclampsia and Eclampsia

- preeclampsia affects 7-10% of pregnancies

- maternal hypertension, proteinuria, peripheral oedema, coagulation abnormalities, varying degrees of DIC

- hyperreflexia and convulsions = eclampsia, may be life threatening

- subclinical hepatic disease may be primary manifestation of preeclampsia, as part of a syndrome of

haemolysis, elevated liver enzymes, and low platelets - HELLP syndrome

Acute Fatty Liver of Pregnancy (AFLP)

- subclinical hepatic dysfunction (elevated LFTs) to hepatic failure, coma, and death

- latter half of pregnancy, usually third trimester

- bleeding, nausea, vomiting, jaundice, and coma

- 30% - presenting symptoms may be those of coexistent preeclampsia

Intrahepatic Cholestasis of Pregnancy

- onset pruritus third trimester, darkening urine and occasionally light stools and jaundice

- serum bilirubin (mostly conjugated) mildly elevated, ALP slightly elevated

- biopsy reveals mild cholestasis without necrosis

- risk for gallstones and malabsorption, ↑ incidence fetal distress, stillbirths, prematurity

Benign Neoplasms

- most are cavernous hemangiomas, blood vessel tumours

- discrete red-blue, soft nodules, usually less than 2 cm

- clinical significance: not mistaken for metastatic tumours, biopsies not done

- benign neoplasms developing from hepatocytes called liver cell adenomas

- young women who have used oral contraceptives and regress on discontinuation

- clinical significance for three reasons:

� may present as intrahepatic mass, mistaken for HCC

� subcapsular adenomas - tendency to rupture, particularly during pregnancy

� rarely contain HCC

Malignant Tumours

- liver and lungs are visceral organs most often involved in metastatic spread of cancer

- primary carcinomas liver relatively uncommon (90% HCC)

- other rare forms: hepatoblastomas and angiosarcomas

Hepatocellular Carcinomas

Pathogenesis:

- three major aetiologic associations:

� viral infection (HBV, HCV)

� chronic alcoholism

� food contaminants (primarily aflatoxins)

- other conditions - tyrosinemia and hereditary hemochromatosis

- other factors interact in development:

- age, sex, chemicals, viruses, hormones, alcohol, nutrition

- pathogenesis different in high-incidence, HBV-prevalent populations vs low-incidence Western populations, where other

chronic liver diseases - alcoholism, HCV, haemochromatosis more common

- development of cirrhosis important, but not requisite, contributor to HCC

The following factors have been implicated:

- repeated cycles cell death and regeneration (as occurs in chronic hepatitis of any cause)

- preneoplastic changes - hepatocyte dysplasia can result from point mutations in selected cellular genes

Clinically: hepatomegaly, RUQ pain, weight loss, elevated αFP

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Death usually occurs from:

(1) cachexia

(2) gastrointestinal or oesophageal variceal bleeding

(3) liver failure with hepatic coma, or, rarely

(4) rupture of tumour with fatal haemorrhage

Cholangiocarcinoma

- malignancy of biliary tree, arising from bile ducts within and outside of liver

- risks: primary sclerosing cholangitis, congenital fibropolycystic diseases of biliary system, previous

exposure to Thorotrast (radiography of biliary tract), liver fluke

- adenocarcinomas

- obstruction to bile flow or symptomatic mass

Metastatic Tumors

- metastatic involvement of liver far more common than primary neoplasia

- most common primaries - breast, lung, and colon

- multiple nodular metastases, hepatomegaly, nodularity of free edge

Biliary Tract

> 95% of biliary tract disease due to cholelithiasis

- up to 1 L bile secreted by liver per day

- bile is stored in gallbladder, capacity about 50 mL

- fat digestion - gallbladder releases stored bile into gut; not essential for biliary function

Cholelithiasis

- 10% to 20% of adult populations

- >80% "silent"

- two main types of gallstones - 80% cholesterol stones, containing more than 50% of crystalline

cholesterol monohydrate

- remainder composed predominantly bilirubin calcium salts and called pigment stones

Risk Factors for Cholesterol Gallstones

Cholesterol Stones

Demography: Native Americans, industrialized countries

Advancing age

Female sex hormones (female, OCP, pregnancy)

Obesity

Rapid weight reduction

Gallbladder stasis (spinal cord injury, pregnancy)

Hypercholesterolaemic syndromes

Pigment Stones

Demography: Asian more than Western

Chronic hemolytic syndromes (sickle cell)

Biliary infection

GI disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

Pathogenesis of Cholesterol Stones:

- cholesterol rendered soluble in bile by aggregation with water-soluble bile salts/water-insoluble lecithins

- when cholesterol concentrations exceed solubilizing capacity of bile (supersaturation), cholesterol can no

longer remain dispersed and nucleates into solid cholesterol monohydrate crystals

- cholesterol gallstone formation involves four simultaneous defects:

1. bile must be supersaturated with cholesterol

2. gallbladder hypomotility promotes nucleation

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3. cholesterol nucleation in bile accelerated

4. mucus hypersecretion traps crystals, permitting aggregation into stones

Pathogenesis of Pigment Stones:

- mixtures abnormal insoluble calcium salts of unconjugated bilirubin with inorganic calcium salts

- infection biliary tract leads to release microbial β-glucuronidases, hydrolyze bilirubin glucuronides

- infection biliary tract - E coli or Ascaris lumbricoides or liver fluke incr likelihood pigment stones

- alternatively, intravascular haemolysis leads to increased hepatic secretion of conjugated bilirubin

Clinical Features:

- 70-80% asymptomatic throughout lives

- biliary pain, constant or colicky

- more severe complications: empyema, perforation, fistulae, cholangitis, and obstructive cholestasis or

pancreatitis

- very small stones can enter CBD

- large stone may erode directly into adjacent loop of small bowel - gallstone ileus

- increased risk for carcinoma of gallbladder

Four contributing factors for cholesterol stones: supersaturation, gallbladder

hypomotility, crystal nucleation, and accretion within gallbladder mucous layer.

Cholecystitis

- inflammation of gallbladder - acute, chronic, or acute superimposed on chronic

- almost always associated with gallstones

Acute Cholecystitis

- acute calculous cholecystitis: acute inflammation of gallbladder, precipitated 90% of time by obstruction

of neck or cystic duct

- primary complication of gallstones

- acute acalculous cholecystitis: in absence of gallstones, generally in severely ill patient

� (1) postoperative state after major, nonbiliary surgery

� (2) severe trauma (MVAs)

� (3) severe burns

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� (4) multi organ failure

� (5) sepsis

� (6) prolonged iv hyperalimentation

� (7) postpartum

Pathogenesis:

- acute inflammation due to gallstone obstruction initiated by chemical irritation of BG by bile acids, with

release of inflammatory mediators (lysolecithen, prostaglandins), gallbladder dysmotility, distention and

ischaemia

- bacterial contamination later complication

- severe illness – cholecystitis direct consequence of ischaemic compromise

- acute acalculous cholecystitis result of ischaemia

Contributing factors:

- dehydration and multiple blood transfusions (pigment load)

- gallbladder stasis - hyperalimentation and assisted ventilation

- accumulation of microcrystals of cholesterol (biliary sludge), viscous bile, and gallbladder mucus, causing

cystic duct obstruction

- inflammation and oedema of wall, compromising blood flow

- bacterial contamination and generation of lysolecithins

Morphology:

- enlarged, tense GB, bright red to blotchy green-black with serosal fibrin covering

- contents turbid to purulent

Symptoms:

- RUQ, epigastric pain, mild fever, anorexia, tachycardia, diaphoresis, nausea, vomiting

- only jaundice if CBD obstruction

- acute acalculous cholecystitis more insidious

� gangrene and perforation much higher than in calculous cholecystitis

Complications of acute and chronic cholecystitis:

- bacterial superinfection with cholangitis or sepsis

- gallbladder perforation

- gallbladder rupture with diffuse peritonitis

- biliary enteric fistula

- gallstone ileus

- aggravation pre-existing medical illness (cardiac, pulmonary, renal, liver decompensation)

Chronic Cholecystitis

- sequel to repeated bouts of mild to severe acute cholecystitis or in absence of attacks

- associated with cholelithiasis in 90% cases

- chronic acalculous cholecystitis exhibits symptoms and histology similar

- supersaturation of bile predisposes to both chronic inflammation and stone formation

- microorganisms, usually E. coli and enterococci, cultured from bile in about one third

- symptoms similar to those of acute form

- following long-term coexistence of gallstones and low-grade inflammation

- rarely: extensive dystrophic calcification - porcelain gallbladder, increased risk cancer

Clinical Features:

- recurrent attacks of steady or colicky epigastric or right upper quadrant pain

- nausea, vomiting, and intolerance for fatty food

Disorders of the Extrahepatic Bile Ducts

Choledocholithiasis and Ascending Cholangitis

Choledocholithiasis:

- presence of stones within bile ducts of biliary tree, most derived from GB, or de novo

- asymptomatic or may cause (1) obstruction, (2) pancreatitis, (3) cholangitis, (4) hepatic abscess, (5)

secondary biliary cirrhosis, (6) acute calculous cholecystitis

Cholangitis:

- bacterial infection of bile ducts

- result from any lesion that obstructions bile flow, most commonly choledocholithiasis

- uncommon causes: indwelling stents, tumours, acute pancreatitis, benign strictures, rarely fungi, viruses,

or parasites

22

- bacteria most likely enter biliary tract through sphincter of Oddi

- usually enteric Gram-negative aerobes such as E. coli, Klebsiella, Clostridium, Bacteroides, or

Enterobacter and Group D strep

- fever, chills, abdominal pain, and jaundice

Biliary Atresia

- one third of infants with neonatal cholestasis, 1:10,000 live births

- complete obstruction of lumen of extrahepatic biliary tree within first 3 months of life

Pathogenesis: aberrant intrauterine development extrahepatic biliary tree

Morphology: inflammation and fibrosing stricture of hepatic/CBDs; cirrhosis within 3 to 6 months

Clinically: neonatal cholestasis; normal birth weight, progression of normal stools to acholic stools

Carcinoma of the Gallbladder

- most adenocarcinomas

- gallstones present in 60 - 90% of cases

- Asia - pyogenic and parasitic diseases common, coexistence of gallstones much lower

- ? gallbladders containing stones or infectious agents develop cancer as a result of irritative trauma and

chronic inflammation, bile acids may be carcinogenic

- clinically: symptoms like cholelithiasis, cancer incidenctally found after operation